Impaired Reelin Processing and Secretion by Cajal-Retzius Cells Contributes to Granule Cell Dispersion in a Mouse Model of Temporal Lobe Epilepsy
Impaired Reelin Processing and Secretion by Cajal-Retzius Cells Contributes to Granule Cell Dispersion in a Mouse Model of Temporal Lobe Epilepsy
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DOI：
10.1002/hipo.20793
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发表时间：
2011-09-01
期刊：
影响因子：
3.5
通讯作者：
Fritschy, Jean-Marc
中科院分区：
文献类型：
--
作者：
Duveau, Venceslas;Madhusudan, Amrita;Fritschy, Jean-Marc
Cajal-Retzius 细胞在个体发育过程中通过释放 reelin 调节皮质层压发挥着至关重要的作用。在成人大脑中，它们由位于大脑皮层边缘区和海马裂中的小的钙结合蛋白阳性中间神经元组成。 reelin 信号传导或表达的改变与主要神经系统疾病有关，并且它们是内侧颞叶癫痫 (TLE) 中颗粒细胞分散 (GCD) 的基础。在这里，我们在 TLE 小鼠模型中研究了 Cajal-Retzius 细胞对癫痫海马 reelin 产生的贡献以及 GCD 的分子机制。在成年小鼠单侧海马内注射红藻氨酸诱导癫痫病灶后，我们观察到，由于细胞内积累，Cajal-Retzius 细胞逐渐对 reelin 产生强免疫阳性。该表型类似于 reeler Orleans (reln(orl/orl)) 小鼠中 Cajal-Retzius 细胞的形态，其表达分泌缺陷的 310-kDa reelin 片段。 GCD 可能是由于 Cajal-Retzius 细胞中 reelin 加工异常导致 reelin 分泌不足所致，这一点通过在 reln(orl/+) 小鼠中注射 KA 得到证实，该小鼠诱导了严重的 GCD。此外，KA 处理的野生型小鼠的蛋白质印迹分析显示，类似于 300 kDa reelin 片段的产量增加，证实了异常的蛋白水解加工。使用肉毒杆菌神经毒素 E (BoNT/E) 治疗后未观察到这种效果，肉毒杆菌神经毒素 E 通过长期阻断突触传递来预防 KA 损伤海马中的 GCD。此外，BoNT/E 阻断了 Cajal-Retzius 细胞中 TrkB 的上调，表明 KA 处理的海马中截短的 reelin 的产生是活动依赖性的，并受 BDNF 调节。总而言之，这些数据表明 GCD 是由 BDNF 控制下的 Cajal-Retzius 细胞异常 reelin 处理引起的。我们的研究结果强调了 Cajal-Retzius 细胞在 TLE 中海马神经元重组中发挥的关键作用。 (C) 2010 Wiley-Liss, Inc.
Cajal-Retzius cells play a crucial role during ontogeny in regulating cortical lamination via release of reelin. In adult brain, they comprise small calretinin-positive interneurons located in the marginal zone of the cerebral cortex and in the hippocampal fissure. Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE). Here, we investigated in a mouse model of TLE the contribution of Cajal-Retzius cells to reelin production in epileptic hippocampus and the molecular mechanisms underlying GCD. Following unilateral intrahippocampal Kainic acid injection in adult mice to induce an epileptic focus, we observed that Cajal-Retzius cells gradually became strongly immunopositive for reelin, due to intracellular accumulation. This phenotype resembled the morphology of Cajal-Retzius cells in reeler Orleans (reln(orl/orl)) mice, which express a secretion-deficient 310-kDa reelin fragment. The possibility that GCD might result from abnormal reelin processing in Cajal-Retzius cells, leading to a lack of reelin secretion, was confirmed by KA injection in reln(orl/+) mice, which induced severe GCD. Furthermore, Western blot analysis in KA-treated wildtype mice revealed increased production of similar to 300-kDa reelin fragments, confirming abnormal proteolytic processing. This effect was not seen upon treatment with Botulinum neurotoxin E (BoNT/E), which prevents GCD in KA-lesioned hippocampus by chronic blockade of synaptic transmission. Furthermore, BoNT/E blocked upregulation of TrkB in Cajal-Retzius cells, suggesting that production of truncated reelin in KA-treated hippocampus is activity-dependent and regulated by BDNF. Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF. Our findings highlight the critical role played by Cajal-Retzius cells for hippocampal neuronal reorganization in TLE. (C) 2010 Wiley-Liss, Inc.